Is HSD17B4 p.Pro375= (c.1125C>T) pathogenic?

HSD17B4 p.Pro375= (c.1125C>T) is classified Likely benign in HSD17B4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-12). Absent from gnomAD v4.1; Associated with d-bifunctional protein deficiency.

What condition is associated with HSD17B4 p.Pro375= (c.1125C>T)?

HSD17B4 p.Pro375= (c.1125C>T) is associated with d-bifunctional protein deficiency, Perrault syndrome (ClinVar).

How common is HSD17B4 p.Pro375= (c.1125C>T) in the general population?

HSD17B4 p.Pro375= (c.1125C>T) is absent from gnomAD v4.1 (gnomAD).

How is Bifunctional enzyme deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

HSD17B4 p.Pro375=

c.1125C>T · rs2126781246 · VCV1077650

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

d-bifunctional protein deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.37	GERP -3.6, phastCons 0.17
Overall
CADD	6.909	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HSD17B4
Protein: p.Pro375=
Coding: c.1125C>T
MANE Select: NM_000414
dbSNP: rs2126781246
Type: single nucleotide variant
Location: chr5:119499469 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.65 · 7 PDB
Residue 375: an α-helix; the 'enoyl-coa hydratase 2' region

Full HSD17B4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

d-bifunctional protein deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Perrault syndrome

For Bifunctional enzyme deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

HSD17B4 c.1210-1G>A Pathogenic/Likely pathogenic ★★ same condition
HSD17B4 c.1262-1G>A Likely pathogenic ★★ same condition
HSD17B4 c.1438-1G>A Pathogenic/Likely pathogenic ★★ same condition
HSD17B4 c.1503+1G>A Likely pathogenic ★★ same condition
HSD17B4 c.1573+1G>A Likely pathogenic ★★ same condition
HSD17B4 c.1574-1G>A Likely pathogenic ★★ same condition
HSD17B4 c.1768-1G>A Pathogenic/Likely pathogenic ★★ same condition
HSD17B4 c.1993+1G>A Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/hsd17b4-p-pro375 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown